DESCRIPTION (adapted from the application) Immediately after partial hepatectomy (PH), hepatocytes exhibit alterations in membrane hyperpolarization, ion fluxes, and intracellular pH that induce cell volume changes. Changes in cell-volume can influence gene expression in hepatocytes, and may influence the regenerative potential of the remnant liver. Preliminary data from our lab has [sic] demonstrated activation of MAPKinases and PI3K with induction of transcription factors AP-1 and NF-KB following aniso-osmotic induced cell swelling in Hep G2 cells and primary rat hepatocytes. Furthermore, we have demonstrated increased DNA synthesis at 24 hours and a 20% increase in cellular proliferation at 72 hours following a 10-min. pulse exposure to hypotonic media. Within this context, the central hypothesis for this proposal is that following partial hepatectomy changes in cell volume initiate proliferative signal transduction in the liver. The first specific aim will examine the activation of the PI3K and MAPKinase signal pathways and cell proliferation following induction of cell volume change. PI3K and MAPKinase cascades are activated following cell volume change and are necessary for cell proliferation following PH. The second specific aim will assess the impact of cytoskeletal manipulation on cell-volume regulated PI3K and MAPKinase activation. Preliminary work in our lab has demonstrated a loss of these signal cascades following cytoskeletal disruption. The third specific aim will examine the role of PTEN in cell volume regulated PI3K and MAPKinase signal cascades activation. PTEN appears to be an important gene product that may be involved in cell volume regulated growth regulation by linking the mechanical stress of cytoskeleton change and proliferative signaling. PTEN transfected cells (sense, and an antisense) will be examined for changes in proliferation and downstream signaling following cell volume alteration. The fourth specific aim will test the central hypothesis in the intact model. Rats undergoing 2/3 partial hepatectomy will have concomitant infusion of agents through the portal vein. Changes in PI3K and MAPKinase signal cascades activation and alterations in cell cytoskeleton will be evaluated and correlated with the in vitro observations. The candidate for this award is an Assistant Professor of Surgery and Cell Biology and a recipient of an American College of Surgeons Faculty Fellowship Award with 7 years of clinical training and 2 years of research experience in liver biology. He seeks the award to evolve into an independent investigator of liver growth and signal transduction relevant to hepatocyte proliferation. The environment for this award is the laboratory of Gary Stein who has a strong track record in the field of cell proliferative signal transduction.